This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The human innate immune system has a vast repertoire of tactics that are engaged to detect and attack foreign particles, such as those introduced upon infection with human immunodeficiency virus (HIV). HIV, in turn, has developed an equally impressive arsenal of methods to evade the host defense system. A newly discovered innate immune response highlights this recurring theme of battle between host survival and viral infection. When HIV enters a cell, it encounters APOBEC3G, an antiviral protein, which induces extensive mutations in the HIV DNA to render the virus non-infectious. To elude the DNA mutation, HIV expresses the virion infectivity factor, Vif, which binds APOBEC3G and targets it for destruction by the proteasome, the cellular protein recycling machinery. The overall goal of this project is to establish the chemical and structural principles by which APOBEC3G mutates HIV DNA and the mechanisms by which HIV Vif sequesters APOBEC3G. These objectives will be achieved through an integrated approach that combines data on the kinetics of the enzymatic reaction, biophysical characterization of the proteins and their interactions, and atomic resolution structures of the proteins in complex with key substrates and cofactors. Information gained from these studies will be used to direct structure-based design of chemical compounds that inhibit Vif and protect APOBEC3G from destruction. These Vif inhibitors may lead to a novel class of anti-HIV drugs that fight AIDS, the pandemic affecting over 40 million people worldwide.